Alterations in the function of the medial temporal lobe (MTL) have been described in schizophrenia (SZ). The MTL shows elevated basal perfusion and decreases in task-stimulated activations in SZ, especially in the anterior MTL. The examination of these MTL changes in SZ will be challenging because antipsychotic drugs (APD) - used to treat almost all people with the illness - attenuate these behavioral and functional alterations; therefore, the studies here proposed will necessarily involve untreated (SZ-off) as well as treated (SZ-on) volunteers with schizophrenia. Now is an optimal time to characterize these MTL functions in schizophrenia because of the sophisticated research tools available to determine regional neuronal activity in brain, the rich advances in cognitive neuroscience, and the focus of SZ research on cognition. It is a propitious time to examine mechanisms associated with hippocampal dysfunction in schizophrenia given the multiple efforts to develop treatments for cognition, treatments that may affect the MTL. Examination of the MTL abnormalities in SZ as described in this proposal will require assessment of both perfusion and task-stimulated activity, since both appear altered, may interact with each other and may be differentially reflected in two of the SZ symptom domains, psychosis and cognition. Current imaging methods allow for a standard- and a high-resolution examination of MTL, so we will pursue both the standard-resolution whole brain approach to test which CNS areas overall are altered during declarative memory tasks in SZ along with the MTL, as well as the high- resolution (high-res), focused method to test which subfields of hippocampus are altered in SZ and to associate these changes with symptoms of the illness. Under both conditions, we will examine the effect of APD treatment on perfusion and activation. One of the ultimate goals in exploring the effects of APD on MTL memory function in schizophrenia is the promise of discovering a more direct, possibly more efficient, pharmacological approach for correcting altered MTL-associated symptoms in the illness. This proposal suggests, not that the MTL is the only region associated with pathology in SZ, but rather that it is a critical player in the overall expression of psychopathology and a good model region in which to examine a new formulation for symptoms. What we propose in this application is to examine memory performance and MTL function in SZ to determine the nature, extent, and circumstances of the changes in MTL neuronal activity in schizophrenia. This project represents a close collaboration between two laboratories, one focused on schizophrenia studies (Tamminga at UTSW) and the other on human memory mechanisms (Wagner at Stanford), together attempting to translate basic cognitive neuroscience to the understanding of symptom domains in SZ. Although this proposal includes only the experiments in SZ, it is based on extensive collaboration between the two sites, involving interactions around concepts and paradigms, shared methodology, and analytic approaches. PUBLIC HEALTH RELEVANCE: Schizophrenia is an illness without known pathophysiology or etiology. However, defining domains of symptomatology, namely, psychosis and cognitive dysfunction, has allowed the formulation of a new model for the illness. This formulation includes recent discoveries from molecular and functional neuroscience and suggests that one primary lesion (associated with the cognitive dysfunction) sets up an altered metaplasticity process in downstream tissue targets, which is then associated with psychosis. We propose to test the elements of this model with in vivo brain imaging using measures of basal activity and relational memory probes, correlating alterations in neural activity with characteristics of the illness.